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I1111111111111111 1111111111 111111111111111 IIIII 11111 111111111111111 IIII IIII USO 10124008B2 c12) United States Patent (IO) Patent No.: US 10,124,008 B2 Lakkaraju et al. (45) Date of Patent: Nov. 13, 2018 (54) USE OF INHIBITORS OF ACID (56) References Cited SPHINGOMYELINASE TO TREAT ACQUIRED AND INHERITED RETINAL FOREIGN PATENT DOCUMENTS DEGENERATIONS WO 9718815 A2 5/1997 (71) Applicant: Wisconsin Alumni Research WO 0007584 A2 2/2000 Foundation, Madison, WI (US) WO 2005097121 Al 10/2005 WO 2009023299 A2 2/2009 (72) Inventors: Aparna Lakkaraju, Madison, WI (US); Kimberly A. Toops, Sun Prairie, OTHER PUBLICATIONS WI (US); Li Xuan Tan, Madison, WI (US) Van Leeuwen et al. Ophthalmology, 2004, vol. 111, pp. 1169-1175.* Kolzer et al. FEBS Letters, 2004, Iss. 559, pp. 96-98.* (73) Assignee: Wisconsin Alumni Research Opreanu et al. Diabetes, 2011, vol. 60, pp. 2370-2378.* Foundation, Madison, WI (US) Ambati, et al., Mechanisms of age-related macular degeneration, Neuron, 2012, 75(1), 26-39. ( *) Notice: Subject to any disclaimer, the term ofthis Arroyo, A 76-Year-Old Man With Macular Degeneration, JAMA, patent is extended or adjusted under 35 2006, 295(20):2394-2406. Barmada, et al., Autophagy induction enhances TDP43 turnover and U.S.C. 154(b) by O days. survival in neuronal ALS models, Nature Chemical Biology, 2014, (21) Appl. No.: 14/746,221 10, 677-685. Bentley, et al., Tarnoxifen Retinopathy: A Rare But Serious Com­ (22) Filed: Jun. 22, 2015 plication, British Medical Journal, 1992, 304:495-496. Cunningham, et al., Clofazamine-Induced Generalized Retinal Degen­ (65) Prior Publication Data eration, Retina, 1990, 10:131-134. Doukas, et al., Topical administration of a multi-targeted kinase US 2015/0366876 Al Dec. 24, 2015 inhibitor supresses choroidal neovascularization and retinal edema, Journal of Cellular Physiology, 2008, 216(1), 29-37. Edward, et al., Amelioration of Light-Induced Retinal Degeneraiton Related U.S. Application Data by a Calcium Overload Blocker, Arch. Ophthalmol., 1991, 109:554- 562. (60) Provisional application No. 62/015,753, filed on Jun. Ewe, et al., Bilateral Maculopathy Associated with Sertraline, 23, 2014. Australasian Psychiatry, 2014, 22(6):573-575. Gannnons, Topical antiangiogenic SRPKl inhibitors reduce choroidal (51) Int. Cl. neovascularization in rodent models of exudative AMD, IOVS, A61K 31155 (2006.01) 2013, 54(9), 6052-6062. A61K 31/136 (2006.01) Grumati, et al., Autophagy is defective in collagen VI muscular A61K 9/00 (2006.01) dystrophies, and its reactivation rescues myofiber degeneration, A61K 311454 (2006.01) Nature Medicine, 2010, 16, 1313-1320. A61K 311445 (2006.01) Gulbins, et al., Acid sphingomyelinase-ceramide system mediates A61K 45106 (2006.01) effects of antidepressant drugs, Nature Medicine, 2013, 19, 934- A61K 31/135 (2006.01) 938. A61K 311137 (2006.01) Hardisty, et al., Citaloprarn-Associated Central Retinal Vein Occlu­ A61K 31/138 (2006.01) sion, Int. Ophthalmol., 2009, 29:303-304. Jimenez-Sanchez, The Hedgehog signaling pathway regulates A61K 31/343 (2006.01) autophagy, Nature Communications, 2012, 3(1200), 1-11. A61K 3114422 (2006.01) Kirkegaard, et al., Hsp70 stabilizes lysosomes and reverts Niemann­ A61K 311451 (2006.01) Pick disease-associated lysosomal pathology, Nature, 2010, 463(7280), A61K 3114525 (2006.01) 549-553. A61K 31146 (2006.01) Kolzer, et al., Interactions of acid sphingomyelinase and lipid A61K 3115415 (2006.01) bilayers in the presence of the tricyclic antidepressant desiprarnine, A61K 311675 (2006.01) FEBS Letters, 2004, 559, 96-98. (52) U.S. Cl. (Continued) CPC ............ A61K 31155 (2013.01); A61K 9/0048 (2013.01); A61K 31/135 (2013.01); A61K Primary Examiner - Samira J Jean-Louis 31/136 (2013.01); A61K 311137 (2013.01); (74) Attorney, Agent, or Firm -Quarles & Brady LLP A61K 31/138 (2013.01); A61K 31/343 (2013.01); A61K 311445 (2013.01); A61K (57) ABSTRACT 3114422 (2013.01); A61K 311451 (2013.01); A method of treating retinal diseases is disclosed that A61K 311454 (2013.01); A61K 3114525 includes the step of administering an effective amount of a (2013.01); A61K 31146 (2013.01); A61K composition including an ASMase inhibitor to a retinal 3115415 (2013.01); A61K 311675 (2013.01); disease patient, wherein at least one disease symptom is A61K 45106 (2013.01) either lessened or progression of the symptom is delayed. (58) Field of Classification Search CPC .............................. A61K 31/55; A61K 31/136 10 Claims, 13 Drawing Sheets See application file for complete search history. (13 of 13 Drawing Sheet(s) Filed in Color) US 10,124,008 B2 Page 2 (56) References Cited Dannhausen, K., M. Karlstetter, A. Caramoy, C. Volz, H. Jagle, G. Liebisch, 0. Utermohlen, and T. Langmann. 2015. Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia OTHER PUBLICATIONS behavior and disturbed retinal function. Biochem Biophys Res Commun. 464:434-440. Kornhuber, et al., Functional inhibitors of acid sphingomyelinase Fan, J., B.X. Wu, and C.E. Crosson. 2016. Suppression of Acid (FIASMAs): A novel pharmacological group of drugs with broad Sphingomyelinase Protects the Retina from Ischemic Injury. Invest clinical applications, Cellular Physiology and Biochemistry, 2010, Ophthalmol Vis Sci. 57:4476-4484. 26, 9-20. Feskanich, D., E. Cho, D.A. Schaumberg, G.A. Colditz, and S.E. Lajunen, et al., Topical drug delivery to retinal pigment epithelium Hankinson. 2008. Menopausal and reproductive factors and risk of with microfluidizer produced small liposomes, European Journal of age-related macular degeneration. Arch Ophthalmol. 126:519-524. Pharmaceutical Sciences, 2014, 62, 23-32. Fox, T.E., X. Han, S. Kelly, A.H. Merrill, 2nd, R.E. Martin, R.E. Lakkaraju, et al., Low-density lipoprotein receptor-related protein Anderson, T.W. Gardner, and M. Kester. 2006. Diabetes alters mediates the endocytosis of anionic liposomes in neurons, Journal sphingolipid metabolism in the retina: a potential mechanism of cell of Biological Chemistry, 2002, 277(17), 15085-15092. death in diabetic retinopathy. Diabetes. 55:3573-3580. Lakkaraju, et al., The lipofuscin fluorophore A2E perturbs choles­ Fraser-Bell, S., J. Wu, R. Klein, S.P. Azen, and R. Varma. 2006. terol metabolism in retinal pigment epithelial cells, PNAS, 2007, Smoking, alcohol intake, estrogen use, and age-related macular 104(26), 11026-11031. degeneration in Latinos: the Los Angeles Latino Eye Study. Am J Le Guezennec, et al., Wipl-dependent regulation of autophagy, Ophthalmol. 141:79-87. obesity, and atherosclerosis, Cell Metabolism, 2012, 16(1), 68-80. Frouws, M.A., B.G. Sibinga Mulder, E. Bastiaannet, M.M. Zanders, Lee, et al., Acid sphingomyelinase modulates the autophagic pro­ M.P. van Herk-Sukel, E.M. de Leede, B.A. Bonsing, J.S. Mieog, cess by controlling lysosomal biogenesis in Alzheimer's disease, C.J. Van de Velde, and G.J. Liefers. 2017. No association between JEM, 2014, 211(8), 1551-1570. metformin use and survival in patients with pancreatic cancer: An Nixon, The role of autophagy in neurodegenerative disease, Nature observational cohort study. Medicine (Baltimore). 96:e6229. Medicine, 2013, 19, 983-997. Gandini, S., M. Puntoni, B.M. Heckman-Stoddard, B.K. Dunn, L. Pampliega, et al., Functional interaction between autophagy and Ford, A. DeCensi, and E. Szabo. 2014. Metformin and cancer risk ciliogenesis, Nature, 2013, 502, 194-200. and mortality: a systematic review and meta-analysis taking into Penfold, et al., Modulation of major histocompatibility complex account biases and confounders. Cancer Prev Res (Phila). 7:867- class II expression in retinas with age-related macular degeneration, 885. Invest Ophthalmol Vis Sci, 1997, 38(10), 2125-2133. Klein, R., B.E. Klein, S.C. Jensen, K.J. Cruickshanks, K.E. Lee, Petersen, et al., Transformation-associated changes in sphingolipid L.G. Danforth, and S.C. Tomany. 2001. Medication use and the metabolism sensitize cells to lysosomal cell death induced by 5-year incidence of early age-related maculopathy: the Beaver Dam inhibitors of acid sphingomyelinase, Cancer Cell, 2013, 24(3), Eye Study. Arch Ophthalmol. 119: 1354-1359. 379-393. Kornhuber, J., P. Tripal, M. Reichel, C. Muhle, C. Rhein, M. Radu, et al, Bisretinoid-mediated complement activation on retinal Muehlbacher, T.W. Groemer, and E. Gulbins. 2010. Functional pigment epithelial cells is dependent on complement factor H Inhibitors of Acid Sphingomyelinase (FIASMAs ): a novel pharma­ haplotype, Journal of Biological Chemistry, 2014, 289(13), 9113- cological group of drugs with broad clinical applications. Cellular 9120. physiology and biochemistry : international journal of experimental Roth, et al., Potent and selective inhibitors of acid sphingomyelinase cellular physiology, biochemistry, and pharmacology. 26:9-20. by bisphosphonates, Angewandte Chemie International Edition, Pikuleva, I.A., and C.A. Curcio. 2014. Cholesterol in the retina: The 2009, 48, 7560-7563. best is yet to come. Prog Retin Eye Res. Rotstein, et al., Regulating Survival and Development in the Retina: Suissa, S. 2012. Randomized Trials Built on Sand: Examples from Key Roles for Simple Sphingolipids, Journal of Lipid Research, COPD, Hormone Therapy, and Cancer. Rambam Maimonides Med 2010, 51:1247-1262. J. 3:e0014. Sander, 587: The Astemizole Retinopathy Trial: Effect of Astemizol Suissa, S., and L. Azoulay. 2012. Metformin and the risk of cancer: on Diabetic Macular, Investigative Ophthalmology & Visual Sci­ time-related biases in observational studies. Diabetes Care. 35 :2665- ence: Annual Meeting of the Association for Research in Vision and 2673. Ophthalmology, Association for Research in Vision and Ophthal­ Toops, K.A., L.X. Tan, Z. Jiang, R. Radu, and A. Lakkaraju. 2015. mology, 2000, 41(4):Sll4. Toops, et al., A detailed three-step protocol for live imaging of Cholesterol-mediated activation of acid sphingomyelinase disrupts intracellular traffic in polarized primary porcine RPE monolayers, autophagy in the retinal pigment epithelium. Mo! Biol Cell. 26: 1-14. Experimental Eye Research, 2014, 124, 74-85. Wu, B.X., J. Fan, N.P. Boyer, Rim. Jenkins, Y. Koutalos, Y.A. Toops, et al., Cholesterol-mediated activation of acid sphingomyelinase Hannun, and C.E.
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